This laboratory has investigated the fundamental question of how the immune system is activated. In particular, we have focused on the molecular mechanisms underlying the activation of T cells, a key step during an immune response. The initial approach to gain fundamental insights into the early phase of activation of human primary T lymphocytes involved the isolation and characterization of novel mitogen- and antigen-inducible genes, including cytokines, transmembrane proteins, a nuclear phosphatase, a ras-related protein and six different transcription factors. Two of these originally cloned factors (p50 and p50B) are members of the Rel-related protein family, a family which also includes c-Rel, p65 and RelB and from which the dimeric NF-kappaB transcription factor complexes are generated. The NF-kappaB complexes are an important component of the immune response; they are essential to the regulated expression of many immunomodulatory proteins, acute phase proteins and viruses, including the human immunodefieceny virus (HIV). Upon antigen- or cytokine- or stress-mediated signalling NF- kappaB is released from a cytoplasmic inhibitor called IkappaB to translocate to the nucleus. Recently we have discovered that the activation of NF-kappaB involves a rapid proteolytic degradation of the inhibitory IkappaB protein. We have also discovered that the newly activated nuclear NF-kappaB induces expression of its own inhibitor, IkappaB, which in turn strives to restore the inhibited state again. Therefore activation is self-limiting and transient. Bcl-3 is an oncoprotein which is structurally related to IkappaB, but which helps to transactivate through kappaB sites, rather than inhibit like IkappaB. It can associate directly with p50B homodimers on DNA and transform these non-transactivating complexes into transactivating ones by means of activation domains present on Bcl-3. This provides a novel by-pass mechanism for activation through kappaB sites, independent of signalling through IkappaB and dependent only on expression of Bcl-3 and p50B.